BDNF and other neurotrophins (NTs) have widespread and powerful roles in mammalian nervous system, and are thought to be involved in a number of psychiatric and neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Rett syndrome, drug addiction, schizophrenia, and depression. However, how NTs function at the cellular and synaptic levels is not well understood. In particular, it is not clear whether they are released from or act on the pre- or postsynaptic neuron. Aplysia sensory-motor neuron synapses in isolated cell culture are an ideal system for addressing those types of questions. An Aplysia BDNF-like NT and its Trk-like receptor have recently been identified and shown to be important for the induction of long-term facilitation (LTF) and growth of presynaptic varicosities. I now propose to use the Aplysia culture system to examine the pre- and postsynaptic roles of ApNT in two learning-related forms of synaptic plasticity, LTF and intermediate-term facilitation (ITF) by the neuromodulator 5HT. NTs do not act in isolation, but are often part of signaling cascades. For example, synaptic growth during development involves a cascade of pre- and postsynaptic changes and back-and-forth signaling by a variety of molecules including NTs and the transmitter itself. Disorders of this synaptic growth cascade are thought to contribute to a number of neurodevelopmental diseases including schizophrenia and Rett syndrome, which also involve NTs. We will investigate the general hypothesis that long-term plasticity involves a similar growth cascade, and specifically examine the role of ApNT and its relationship with spontaneous transmitter release as key players in such a cascade. Recent studies in Aplysia suggest that spontaneous release recruits postsynaptic mechanisms of ITF, and then retrograde signaling contributes to recruiting presynaptic mechanisms of LTF. Preliminary results suggest that ApNT plays an important role and could act as such a retrograde signal, although it might also function as an autocrine or anterograde signal. In addition, spontaneous release may enhance ApNT and ApNT may also enhance spontaneous release, perhaps creating positive feedback loops that would make the cascade more dynamic. To further explore the possible roles of ApNT and spontaneous release in a trans-synaptic signaling cascade leading to long-term synaptic plasticity and growth, we will (1) examine pre- and postsynaptic sources and targets of ApNT during LTF and ITF, (2) examine the roles of ApNT and spontaneous release in the assembly of pre- and postsynaptic components during LTF and ITF, and (3) examine possible interactions between ApNT and spontaneous release during LTF and ITF. These studies may also suggest how dysfunctions of this cascade could contribute to psychiatric and neurological disorders.